To date, protein active ingredients, thus sensitive to digestive enzymes, in particular insulin and analogues thereof (more precisely sensitive to proteases, such as pepsin in the stomach and principally trypsin in the intestine), remain essentially administered by parenteral route in spite of numerous studies that have been undertaken to investigate alternate routes of delivery (in particular those more comfortable for patients).
The article by Simona Cernea and Itamar Raz, published in Timely Top. Med. Cardiovasc. Dis. 2006 Nov. 1; Vol 10: E29, summed up, in 2006, alternatives to administering insulin by injection. A number of patent documents, for example WO 85/05029, U.S. Pat. No. 5,824,638 and WO 2006/127361, also exist on the subject.
The most advanced work is probably that relating to administration by nasal route. This route of administration would indeed be less technically constraining than the parenteral route. The highly vascular nasal mucosa has the capacity to absorb proteins and to transmit them to the blood system, which makes it a potentially good candidate. However, it suffers from a certain difficulty in controlling the dose delivered by inhalers depending on the patient (notably if the patient has a cold, etc.).
According to the prior art, protein active ingredients that have been chemically modified according to numerous variants and those formulated according to numerous variants have more generally been disclosed. Thus:                U.S. Pat. No. 4,692,433 discloses administration by oral route of polypeptide hormones. Said hormones are administered, advantageously in buffered aqueous solutions, encapsulated in a liposome. They are not administered in free form;        documents WO 97/33531, WO 02/072075 and US 2003/0017203 disclose gastro-resistant forms for the administration of peptides by oral route. These forms combine a gastro-resistant coating and a pH-lowering agent. Said coating protects the active ingredient during its passage in the stomach. Once in the intestine, said coating is dissolved, releasing both the active ingredient and the pH-lowering agent. Due to the action of said pH-lowering agent, the pH of the intestine is lowered locally, in fact reducing the proteolytic activity of the intestinal proteases present. Protection in the stomach and in the entry of the intestine is thus ensured by two different means whose action develops successively. The peptides in question intervene neither in free form nor in the presence of a buffer. Incidentally, it should be noted here that table 1 on page 23 of application WO 97/33531 presents results for the bioavailability of buffered solutions of calcitonin. The tests were conducted to study the influence of the pH of the solution administered locally (directly in the intestine of rats) on the absorption of the active ingredient. These tests were conducted in order to optimize the nature of the pH-lowering agent intervening in the gastro-resistant form proposed. These tests neither describe nor suggest the oral compositions of the invention (pharmaceutical compositions or drugs) disclosed below;        application US 2002/0132757 relates to the administration of calcitonin, in the form of solid particles, through epithelial membranes, through oral or nasal mucosa. For this specific type of administration, which does not involve the gastrointestinal tract, the active ingredient is treated as follows. It is first dissolved in a buffer (mere processing aid). The solution obtained, supplemented with one or more surfactants and one or more absorption enhancers, is lyophilized. The dry particles obtained are finally packaged in a pressurized container with a suitable solvent or vehicle (ethanol, for example). The function of this solvent or vehicle is to disperse under pressure said particles over an area, as large as possible, of the mucosae. Said particles are not administered in the presence of a buffer;        application US 2007/0154559 discloses a complicated method of formulating active ingredients for administration by oral route. Improved gastrointestinal absorption is sought. The absorption in question is that of nanoparticles containing said active ingredients. According to the method disclosed, the active ingredient is first dissolved in a buffer (mere processing aid) and then complexed with a counter ion. The complex obtained is placed in solution, in the presence of a polymer and a lipid, in an organic solvent. An emulsion is then generated with the obtained organic solution and an aqueous solution containing an emulsifier. The nanoparticles are finally formed by the evaporation of said organic solvent. Thus, the active ingredient is administered neither in free form nor in the presence of a buffer;        application WO 2007/032018 discloses a complicated method of formulating active ingredients, for administration by oral route, of the same type as disclosed in the US application above. The active ingredient is also delivered in nanoparticle form. Said nanoparticles (fatty acid and polymer-based) are sensitive to pH. They shrink in acidic pH. The active ingredient is thus better protected during its passage in the stomach. Here again, the active ingredient is administered neither in free form nor in the presence of a buffer;        application FR 2,123,524 (corresponding Irish Patent Application No. IE36225B1) discloses an insulin derivative obtained by acylation. The chemical reaction in question is implemented in a buffered medium. Application WO 01/36656 discloses a complex between a biomolecule and hyaluronic acid. These two documents of the prior art neither disclose nor suggest pharmaceutical compositions combining their active ingredient in free form and a protective buffer system.        
The above comments summarize the prior art teaching with respect to the concepts of oral composition, free-form protein active ingredient and buffer. Thus there is a need for a composition for the oral delivery of a protein active ingredient that resists being metabolized in the gastric environment and in the intestinal environment.